| Summary: | Concomitant inhibition of MAPK and PI3K signaling pathways has been recognized as a promising strategy for cancer therapy, which effectively overcomes the drug resistance of MAPK signaling pathway-related inhibitors. Herein, we report the scaffold-hopping generation of a series of 1<i>H</i>-pyrazolo[3,4-<i>d</i>]pyrimidine dual ERK/PI3K inhibitors. Compound <b>32d</b> was the most promising candidate, with potent inhibitory activities against both ERK2 and PI3Kα which displays superior anti-proliferative profiles against HCT116 and HEC1B cancer cells. Meanwhile, compound <b>32d</b> possessed acceptable pharmacokinetic profiles and showed more efficacious anti-tumor activity than GDDC-0980 and the corresponding drug combination (BVD-523 + GDDC-0980) in HCT-116 xenograft model, with a tumor growth inhibitory rate of 51% without causing observable toxic effects. All the results indicated that <b>32d</b> was a highly effective anticancer compound and provided a promising basis for further optimization towards dual ERK/PI3K inhibitors.
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